This invention relates to methods for modulating attention, learning, and memory by controlling carbonic anhydrase activity. More particularly, the invention involves administering a compound that alters carbonic anhydrase activity in the brain thereby affecting establishment of a theta rhythm in the brain.
Acetazolamide is a generic drug manufactured in forms of capsule, tablets or injectable preparations. Inhibition of carbonic anhydrase activity by acetazolamide is a therapeutic approach in use or suggested for several indications, including glaucoma, conjunctive heart failure, mountain sickness, sleep apnea and petit mal seizures (epilepsy), and body fluid retention. These therapeutic avenues are diverse and none of them suggests any cognitive impacts of regulating carbonic anhydrase activity.
Hippocampal theta (xcex8) rhythm (synchronized neuronal discharge) is believed to play a critical role in information processing and memory consolidation during exploratory behavior. Theta activity depends on cholinergic inputs and xcex8 discharges of GABAergic interneurons, and can be induced e.g. by a cholinergic receptor agonist (carbachol). GABA acts as an inhibitor of action potentials by keeping the GABA-Clxe2x88x92 channel open. This channel is an anion transporter, exchanging Clxe2x88x92 for HCO3xe2x88x92. Maintaining the open channel allows Clxe2x88x92 to flow into the cell to hyperpolarize the membrane potential. Cholinergic components depolarize the membrane potential, and if threshold is reached an action potential is created. It is believed that the synchronized depolarization and excitation creates an oscillating membrane potential leading to xcex8 activity, but the mechanism has remained unknown. GABAergic depolarization can be induced by enhancing HCO3xe2x88x92 conductance through GABAA receptor-channels in adult hippocampal cells, a response sensitive to carbonic anhydrase inhibitors (Kaila ""93). However, no association has previously been identified between carbonic anhydrase inhibition at the cellular-electrophysiological level on the one hand, and a reduction in theta rhythm on the other.
There have been few medications suitable for improving attention in those who need it, and no effective medications for those who need to suppress learning painful memories. There is a need to elucidate a simple biochemical target for controlling the extremely complicated brain-wide effect of theta rhythm, and the even more complex events leading to attention and learning. Such a target would be invaluable in identifying specific compounds for achieving the desired cognitive effects.
This invention differs from the prior art in modifications, which were not previously known or suggested, including the use of carbonic anhydrase regulators to alter theta rhythm and produce cognitive effects in mammals. The methods of the invention provide advantages that were not previously appreciated, such as the ability to selectively enhance attention and learning. This invention satisfies a long felt need for compounds that selectively enhance or inhibit attention and learning.
The widespread use of acetazolamide, with no substantial cognitive side effects reported, makes it surprising to discover that the compound does inhibit spatial learning in animals, and presumably in humans. This invention thus identifies a previously unrecognized problem, and shows how to solve it, e.g. by careful dosing regimens of acetazolamide so as to reduce its cognitive side effects.
Acetazolamide, a drug commonly used for glaucoma and diuresis, has been found to specifically block acquisition of new memories. Post-traumatic stress disorder involves learning new contexts for traumatic memories. These new contexts would be blocked during the administration of acetazolamide. Thus, acetazolamide can be used for short-term memory suppression, for example to prevent post traumatic stress syndrome during a period of trauma.
More generally, based on comprehensive electrophysiologic studies of GABAergic depolarization of CA1 hippocampal cells, we have implicated bicarbonate conductance enhancement as critical for theta rhythm and spatial maze learning. Bicarbonate-mediated GABAergic depolarization mediated by carbonic anhydrase (blocked by acetazolamide) is a target for drugs that either block or enhance new memory formation. Blocking drugs would have application in post-traumatic stress disorders and related diseases. Cognitive enhancing drugs would have wide application in the treatment of neurodegenerative disorders, especially those involving dementia.
Surprisingly, according to the invention, the GABAergic transformation is associated with establishment of a theta rhythm, and both phenomena can be controlled together by modifying neuronal carbonic anhydrase activity. Although it was previously thought that the transformation was related to attention, and that the theta rhythm was associated with attention, there was no teaching that the two were intimately connected and subject to common control via carbonic anhydrase inhibitors or activators.
The invention relates to a method for blocking associative memory acquisition comprising determining a need for blocking, and administering an inhibitor, such as acetazolamide, of carbonic anhydrase activity in the brain, thereby blocking the memory acquisition. The method can also be used for suppressing attention, learning and/or memory formation in a mammal comprising determining a need for suppressing, and administering an inhibitor of carbonic anhydrase activity in an amount effective to inhibit carbonic anhydrase activity in the brain, preferably in neurons. The inhibitor may be selected from the group consisting of acetazolamide, benzolamide, and analogs thereof. An analog is a molecule having a structure function relationship similar to the named compound that allows it to bind to and inhibit carbonic anhydrase in the brain. Although, the inhibitor prevents establishment of a theta rhythm during learning, it does not affect memory retrieval from formed memories, or sensory or locomotor behaviors.
In yet another aspect of the invention, the method can be used for improving attention and/or memory acquisition in a patient comprising determining the need for improved attention and/or memory acquisition, and administering to the patient a stimulator of intraneuronal carbonic anhydrase activity in an amount sufficient to stimulate intraneuronal carbonic anhydrase activity. The patient may be healthy, i.e. have no neurodegenerative disorder or the patient may suffer from a neurodegenerative disease. The invention may also be used for treating a neurodegenerative disorders comprising administering an effective amount of a stimulator of intraneuronal carbonic anhydrase activity. The cognitive ability may be enhanced. The neurodegenerative disease can also be dementia.
The invention further provides a method for modulating attentive cognition comprising administering a compound that alters intraneuronal carbonic anhydrase activity in an amount sufficient to affect the establishment of a theta rhythm. The theta rhythm can be affected by modulating bicarbonate-mediated GABAergic depolarization. Moreover, the attentive cognition may be selected from memory formation, learning, spatial memory, and attention. In one aspect the modulating is stimulating. The compound can be administered in an amount sufficient to inhibit intraneuronal carbonic anhydrase activity, establish of a theta rhythm, and suppress memory acquisition. The compound may also be administered in an amount that does not affect memory retrieval. Moreover, the suppression may occur about one half to one hour after administering the inhibitor compound.
The term xe2x80x9cattentive cognitionxe2x80x9d is meant to encompass memory formation, learning, spatial memory, and attention. The inhibiting of carbonic anhydrase is preferably selective in that it reduces memory acquisition, but not memory retrieval.
In another aspect of the invention, the method may be used for modulating memory and attention by switching theta rhythm on and off to modulate intraneuronal carbonic anhydrase activity, comprising administering a compound that modulates intraneuronal carbonic anhydrase activity. The modulating intraneuronal carbonic anhydrase activity may comprise increasing intraneuronal carbonic anhydrase activity or alternatively decreasing intraneuronal carbonic anhydrase activity.
In yet a further aspect, the invention relates to a method of altering memory acquisition by modulating HCO3xe2x88x92 conductance comprising administering a compound that modulates carbonic anhydrase activity the brain in an amount sufficient to alter HCO3xe2x88x92 conductance. The compound can be administered in an amount sufficient to modulate the HCO3xe2x88x92 current relative to the Clxe2x88x92 and K+ currents. The invention also relates to a method of modulating establishment of a theta rhythm comprising administering a compound that modulates intraneuronal carbonic anhydrase activity in an amount sufficient to control the occurrence of synaptic transformation. Another aspect of the invention relates to a method for treating a neurological disorder comprising administering a compound that stimulates intraneuronal carbonic anhydrase activity in an amount sufficient to control the occurrence of synaptic transformation. The neurological disorder can be associated with a disorder affecting cognition such as stroke, hypoxia, and ischemia, and others known to practitioners.
The invention may also relate to a method for screening compounds for usefulness for cognitive enhancement therapy comprising measuring the effect of a compound on carbonic anhydrase activity in neurons, in tissue, in animals, or in cell culture, and selecting those compounds that stimulate carbonic anhydrase activity. In addition, the invention provides a method for screening compounds for usefulness for cognitive enhancement therapy comprising measuring the effect of a compound on theta rhythm in neurons, in tissue, in animals, or in cell culture and selecting those that establish a theta rhythm.
Finally, the invention provides a method of blocking synaptic transformation of inhibitory postsynaptic potentials into excitatory postsynaptic potentials in GABAergic synapses in a mammalian brain, comprising determining a need for blocking, and administering to the brain an inhibitor of intraneuronal carbonic anhydrase activity, thereby blocking the synaptic transformation in the synapses. The inhibitor may neutralize the excitatory effects of a memory related signaling protein. The memory related signaling protein can be calexcitin and the inhibitor can be acetazolamide or an analog of acetazolamide. The metabolic pathway of the compound preferably involves bicarbonate-mediated GABAergic depolarization. The affected synapses may be found in circuits throughout the brain, including pyramidal cells in the hippocampal region.
The invention also relates to a pharmaceutical product comprising a dosage form comprising a pharmaceutically acceptable carrier and a compound that inhibits or stimulates carbonic anhydrase activity in the brain, associated with labeling indicating use of the dosage form for cognitive effects.
Further objectives and advantages will become apparent from a consideration of the description, drawings, and examples.